Meso-substituted tripyrrane compounds, compositions, and methods for making and using the same

ABSTRACT

The invention provides for tripyrrane compounds of the formula ##STR1## wherein: each Q represents, typically, an alkyl group, cycloalkyl group, aryl group, or a heteroaryl group; and each R represents hydrogen, an alkyl group, alcohol group, or a carbonyl-containing group. Additionally, there are described methods to prepare such compounds, for example, comprising the steps of: 
     (a) reacting a compound of the formula: 
     
         Q--CHO or Q--CH(OS)(OS&#39;) 
    
     wherein S and S&#39; are independently lower alkyl, an aryl group containing from 5 to 14 ring atoms, and --(CH 2 ) n  -- where n=2-4; 
     with a stoichiometric excess of a pyrrole having the formula: ##STR2## in the presence of a catalytic amount of an acid; (b) removing the unreacted pyrrole or any other solvents used in (a) by evaporation to form a residue; and 
     (c) treating the residue to remove high molecular weight polymeric materials and the corresponding dipyrromethane by-product, leaving the desired compound.

The present application is a continuation of U.S. Ser. No. 08/612,215,filed Mar. 7, 1996, an allowed application, the complete text andfigures of which are hereby incorporated by reference as if fully setforth.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to certain meso-substituted tripyrranecompounds, compositions containing them, their preparation, and theiruse as key intermediates in synthesizing 5,10-disubstituted porphyrincompounds or other 5,10-disubstituted polypyrrolic macrocycles. Inparticular, the invention relates to the use of a one-step synthesis ofmeso-substituted tripyrranes, which offers considerable advantages withrespect to the large scale, industrial production of meso-substitutedporphyrins and other polypyrrolic macrocycles. Many of themeso-substituted porphyrins and polypyrrolic macrocycles made in thisway are useful as:

photosensitizers for photodynamic therapy;

chelators for radionuclides;

MRI contrast agents (i.e., chelators for paramagnetic metals);

other biomedical uses; and

technical uses for infrared absorbing dyes, such as imaging, datarecording and printing.

2. Description of the Related Art

β-alkyl substituted tripyrrane compounds have been recognized asimportant building blocks for synthesizing a wide variety ofpolypyrrolic macrocyclic systems. For example, in 1972, Broadhurst etal. condensed a bis(pyrrolylmethyl)pyrrole diacid with a similartwo-ring component, specifically, a β-alkyl dipyrrin dialdehyde, to forma 22 π-electron macrocycle containing five pyrrolic rings, which wasnamed "sapphyrin." Broadhurst et al., "The Synthesis of 22 π-ElectronMacrocycles. Sapphyrins and Related Compounds", J.C.S. Perkin I, 2111-16at 2112 (1972). Other workers made further contributions along the samelines, as follows:

    ______________________________________    Year    Reported   Description    Source    ______________________________________    1983       Condensed a β-alkyl                              Rexhausen et al.,               tripyrrane     "Synthesis of a New               dialdehyde with                              22 π-Electron               a dipyrrylmethane                              Macrocycle:               to produce a   Pentaphyrin", J.               pentaphyrin.   Chem. Soc., Chem.                              Commun., 275.    1983       Coupled a      Bauer et al.,               bipyrroledicar-                              "Sapphyrins: Novel               boxaldehyde with a                              Aromatic               β-alkyl tripyrrane                              Pentapyrrolic               diacid to      Macrocycles", J.               synthesize deca-                              Am. Chem. Soc.,               methylsapphyrin.                              105, 6429-36 at                              6431.    1987       Used an acid-  Sessler et al.,               catalyzed 1:1  "Synthesis and               Schiff base    Crystal Structure               condensation of                              of a Novel               o-phenylenediamine                              Tripyrrane-               or 1,4-diamino-                              Containing               butane with a  Porphyrinogen-like               β-alkyl diformyl-                              Macrocycle", J.               tripyrrane to form                              Org. Chem., 52,               a macrocycle having                              4394-97 at 4395.               saturated methylene               bridges to link the               pyrrole subunits.    1990 and   Condensed an   Sessler et al.,    1992       α-dicarboxyalde-                              U.S. Pat. Nos.               hyde, β-alkyl                              4,935,498 and               tripyrrane with                              5,162,509 (See               o-phenylenediamine                              FIG. 26).               to form an expanded               porphyrin known as               a "texaphyrin."    1992       Condensed a β-alkyl                              Sessler et al.,               dicarboxylic acid                              "Sapphyrins and               tripyrrane with a                              Heterosapphyrins",               diformyl bipyrrole                              Tetrahedron, 48:44,               under acidic   9661-72 at 9663.               conditions in the               presence of oxygen               to give a deca-               alkylsapphyrin.    1992       Performed an acid-                              Sessler et al., "A               catalyzed 1:1  Nonaromatic               condensation of                              Expanded Porphyrin               1,8-diaminoanthra-                              Derived from               cene and a β-alkyl                              Anthracene -- A               diformyl tripyrrane                              Macrocycle Which               to form an expanded                              Unexpectedly Binds               porphyrin.     Anions", Angew.                              Chem. Int. Ed.                              Engl., 31:4, 452-55                              at 453.    1992 and   Condensed 4,4'-                              Sessler et al.,    1994       diethyl-5,5'-  U.S. Pat. Nos.               diformyl-3,3'- 5,302,714 (FIGS.               dimethyl-2,2'- 1C and 5D) and               bipyrrole and 2,5-                              5,159,065.               bis(5-carboxy-3-               ethyl-4-methyl-               pyrrol-2-ylmethyl)-               3,4-diethylpyrrole               to produce               3,8,12,13,17,22-               hexaethyl-               2,7,18,23-               tetramethyl-               sapphyrin.    1993       Reacted a β-alkyl                              Charriere et al.,               tripyrrane     "The Chemistry of               dialdehyde with the                              Polyphyrins 2,               corresponding α,α'-                              Synthesis of               unsubstituted  Hexaphyrins and               tripyrrane to  their Metal               afford, after  Complexes",               oxidation with Heterocycles, 36:7,               iodine and     1561-75 at 1562.               p-benzoquinone, a               β-peralkyl-               hexaphyrin.    1994       Condensed pyridine-                              Berlin et al., "New               2,6-dicarbaldehyde                              Porphyrinoid               with a β-alkyl                              Macrocycles               tripyrranedicar-                              Containing               boxylic acid, fol-                              Pyridine", Angew.               lowed by oxidation                              Chem. Int. Ed.               to form an 18-π                              Engl., 33:2, 219-20               macrocycle called                              at 219.               "pyriporphin."    1994       Decarboxylated a                              Berlin et al.,               β-alkyl tripyrrane-                              "Benziporphyin, a               dicarboxylic acid,                              Benzene-Containing               condensed it with                              Nonaromatic               isophthaladehyde,                              Porphyrin               and oxidized the                              Analogue", Angew.               product in situ                              Chem. Int. Ed.               with p-chloranil to                              Engl., 33:12, 1246-               give a benzene-                              47 at 1246.               containing               macrocycle called               "benziporphin."    1994       Performed a Schiff                              Sessler et al.,               base condensation                              "Texaphyrins:               between a β-alkyl                              Synthesis and               diformyltripyrrane                              Applications", Acc.               and an aromatic                              Chem. Res., 27, 43-               1,2-diamine, such                              50 at 46.               as o-phenylene-               diamine derivative,               to form an expanded               porphyrin called a               "texaphyrin."    ______________________________________

However, the syntheses of the β-alkyl tripyrranes used above as startingmaterials are generally lengthy and involve several reaction steps.Specifically, when the syntheses of β-alkyl tripyrranes are described,they typically involve: (1) the reaction of an α-free,α'-ester-β-tetraalkyl dipyrromethane and an α-ester,α'-carboxaldehyde-β-dialkylpyrrole and subsequent reduction of thedipyrromethene moiety first formed (e.g., see Bauer et al. at 6431 and6435) or (2) the reaction of anα-acetoxymethyl-α'-ester-β-dialkylpyrrole with an α,α'-freeβ-dialkylpyrrole, subsequent removal of the esters, and diformylation,if required (e.g., see Sessler et al., J. Org. Chem., 52 at 4395; U.S.Pat. Nos. 4,935,498, 5,162,509, 5,159,065 and 5,302,714; Sessler et al.Tetrahedron, 48:44 at 9661-63; Charriere et al., Heterocycles, 36:7 at1567; and Seseler et al., Acc. Chem. Res., 27 at 45). The pyrrolicstarting materials themselves must also be synthesized from simplercompounds, which involves several more reaction steps.

One group of workers has disclosed the reaction at room temperature ofan aldehyde, such as benzaldehyde, with an excess amount of pyrrole inthe absence of a solvent to produce, primarily, a meso-substituteddipyrromethane, which is used as a key building block in the synthesisof linear porphyrin arrays. Lee et al., "One-Flask Synthesis ofMeso-Substituted Dipyrromethanes and Their Application in the Synthesisof Trans-Substituted Porphyrin Building Blocks", Tetrahedron, 50:39,11427-40 (1994). Thin layer chromatography ("TLC") analysis of thereaction mixture showed, in addition to the dipyrromethane product, "atiny amount (<5%) of a tailing component." Lee et al. attempted toisolate the tailing component and "provisionally" assigned it thestructure of "the corresponding tripyrromethane" based on NMRspectroscopy. However, this compound was described as being less stablethan the dipyrromethane primary product and as changing "from a whitesolid to a black material over one day at room temperature." Lee et al.at 11429. No further efforts were made to isolate or confirm theidentity of the impurity speculated to be a "tripyrromethane", and noteachings are provided by Lee et al. with respect to how to make and usethe meso-substituted tripyrranes of the invention. Rather, the focus ofLee et al. is on the dipyrromethane as the desired product of thereaction, as opposed to the tripyrrane.

Rebek et al., J. Tetrahedron Lett., 35, 6823 (1994) mention briefly inthe reference section of their paper a preparation formeso-phenyldipyrromethane by reacting benzaldehyde and pyrrole in thesolvent toluene and in the presence of an acid catalyst, a procedureoriginating from a Ph.D. thesis (T. Carell, Ph.D. thesis,Ruprechts-Karl-Universitat Heidelberg (1994)). However, the productionor other occurrence of any tripyrrane was not disclosed.

When others have tried to react a benzaldehyde directly with pyrrole,they have usually obtained either an inverted meso-tetraphenylporphyrincompound (specifically, 2-aza-21-carba-5,10,15,20-tetraphenylporphyrin,also known by the trivial name "N-confused porphyrin") or a mixture ofthe inverted tetraphenylporphyrin, non-inverted tetraphenylporphyrin,and sapphyrin. See Furuta et al., "`N-Confused Porphyrin`: A New Isomerof Tetraphenylporphyrin", J. Am. Chem. Soc., 116, 767-68 (1994);Chmielewski et al., "Tetra-p-tolylporphyrin with an Inverted PyrroleRing: A Novel Isomer of Porphyrin", Angew. Chem. Int. Ed. Engl., 33:7,779-81 (1994); and Chmielewski et al.,"5,10,15,20-Tetraphenylsapphyrin--Identification of a PentapyrrolicExpanded Porphyrin in the Rothemund Synthesis", Chem. Eur. J., 1:1,68-73 (1995). A dibenzofuranyl pyrromethane resulted wheno-acetoxybenzaldehyde was heated with pyrrole in hot acetic acid.Cavaleiro et al., "An Anomalous Dipyrrole Product from AttemptedSynthesis of a Tetra-arylporphyrin," J. Org. Chem., 53:5847-49 (1988).When pyrrole is reacted with 2,6-dichlorobenzaldehyde and zinc acetate,the solid phase of the reaction mixture was said to contain the desiredporphyrin complex, tetrakis(2,6-dichlorophenyl)porphirato zinc(II), andthe liquid phase was said to contain another product, bis(meso-2,6-dichlorophenyl)-5-(o,o'-dichlorobenzyl)dipyrromethene!zinc(II). Hill et al., "Isolation and Characterization of the PrincipalKinetic Product in the Preparation of a Sterically HinderedTetra-Arylporphyrin: X-ray Structure of a Bis(dipyrromethene) Complex ofZinc, Zn^(II) (C₂₂ H₁₃ Cl₄ N₂)₂.toluene," J. Chem, Soc. Chem. Commun.,1228-29 (1985).

It has now been found that meso-substituted tripyrranes can be made inwhat is virtually a one-step synthesis, sometimes even without requiringthe chromatographic separations usually necessary to purify polypyrrolicmaterials. This means that the subsequent synthesis of polypyrrolicmacrocycles can be greatly simplified. Using the compounds and methodsof the invention, a macrocycle such as meso-diphenylpentaphyrin, forexample, can be prepared in just three steps, as compared with the 10-12steps needed for the meso-unsubstituted, β-alkylated analogue, beginningwith simple pyrrolic compounds and benzaldehyde as starting materials.

Further, meso-substituted macrocycles, such as pentapyrrolicmacrocycles, exhibit considerably altered spectroscopic behavior ascompared with the meso-unsubstituted, β-alkyl counterparts, due at leastin part to the different site of substitution (β only vs. meso and,optionally, also β). When the meso-substituent is aryl or heteroaryl,for example, it also confers significantly different electronicproperties. Further still, the addition of a large, fairly rigid andflat substituents such as aryl groups changes the steric requirements ofthe molecule. This alters the biological properties of meso-substitutedmacrocycles, as compared with their beta-alkyl analogs.

More importantly, the meso-substituents of the compounds of theinvention also provide a way to manipulate the biodistribution andpharmacokinetics of the polypyrrolic macrocycles made from the compoundsof the invention by changing the peripheral substitution patterns.Specifically, the most active photosensitizers used in photodynamictherapy are typically highly amphiphilic in nature. If themeso-substituents on the tripyrrane compounds of the invention arephenyl groups, for example, this presents an opportunity to introducesubstituents on the phenyl groups to fine-tune the amphiphilicity, thespectroscopic properties, and/or the metal binding properties, of theresulting macrocycle even further.

To optimize the biological properties of any compound, it is of greatadvantage to be able to prepare whole "libraries" of related compounds.The alkyl- or aryl-substituents of the tripyrranes of the invention canbe easily reacted with other monocyclic or polycyclic compounds tosynthesize 5,10-disubstituted polypyrrolic macrocycles, giving access tomacrocycles of an almost unlimited variety. Further, these ends areaccomplished in only a few synthetic steps and, potentially, on a largescale.

Thus, the processes of the invention provide efficient methods forproducing libraries of compounds having flexible, "fine-tuned"biological activity, such as precisely delivered photosensitizingability in standard photodynamic therapy protocols.

SUMMARY OF THE INVENTION

According to the present invention, there have been prepared novelmeso-substituted tripyrrane compounds of Formula I: ##STR3## wherein: Qis an alkyl group, a cycloalkyl group having from 5 to 7 ring atoms, oran aryl or heteroaryl group having from 5 to 12 ring atoms and

all R groups are identical hydrogen, alkyl, alcohol, orcarbonyl-containing groups.

The invention also concerns compositions comprising:

(a) from 5 to 100 mole % by weight of a compound of Formula I; and

(b) from 0 to 95 mole % by weight of the dipyrromethane corresponding tothe compound of Formula I.

Further, a method has been found for efficiently synthesizing thecompounds of Formula I. Specifically, in the invention, a method formaking the compound having Formula I comprises the steps of:

(a) reacting a compound of the formula:

    Q--CHO or Q--CH(OS)(OS')

wherein Q is as defined above, and

S and S' are independently lower alkyl, an aryl group containing from 5to 14 ring atoms, and --(CH₂)_(n) -- where n=2-4;

with a stoichiometric excess of a pyrrole having the formula: ##STR4##in the presence of a catalytic amount of a strong Lewis or Bronstedacid; (b) removing the unreacted pyrrole or any other solvents used in(a) by evaporation to form a residue;

(c) treating the residue to remove high molecular weight polymericmaterials and the corresponding dipyrromethane by-product, leaving thecompound of Formula I.

Further, the invention provides processes for making 5,10-disubstitutedporphyrin compounds or other 5,10-disubstituted polypyrrolicmacrocycles. By "5,10-disubstituted polypyrrolic macrocycle" is meant apolypyrrolic macrocycle having at least two meso-substituents atneighboring meso-positions of the macrocycle. The term is intended toinclude polypyrrolic macrocycles having more than two meso-substituents,such as, for example, 5,10,15,20-tetraphenylsapphyrin.

One process comprises the steps of:

(a) cyclizing, in the presence of an acid catalyst, a compound ofFormula I having two terminal pyrrole rings, each with an unsubstitutedα-position: ##STR5## wherein: Q represents identical alkyl groups,cycloalkyl groups having from 5 to 7 ring atoms, or aryl or heteroarylgroups having from 5 to 12 ring atoms and

R represents identical hydrogen, alkyl, alcohol or carbonyl-containinggroups;

with a compound having a formula selected from the group consisting of:##STR6## wherein: S and S' are independently lower alkyl, an aryl groupcontaining from 5 to 14 ring atoms, and --(CH₂)_(n) -- where n=2-4;

R¹ -R⁵ are independently hydrogen, lower alkyl, alcohol orcarbonyl-containing groups;

X and X' are groups capable of coupling with the unsubstitutedα-positions of the terminal pyrrole rings of the compound of Formula I;

Z and Z' are independently --N--, >NH, --O-- or a bivalent sulfur atom;and

Y is a direct link, alkylene, pyrrolylene, furanylene, phenylene,thiophenylene, benzylene, or alkylene-pyrrolene-alkylene, to form acyclized intermediate; and

(b) oxidizing the cyclized intermediate to form the corresponding5,10-disubstituted porphyrin compound or other 5,10-disubstitutedpolypyrrolic macrocycle.

A second process for making a 5,10-disubstituted porphyrin compound orother 5,10-disubstituted polypyrrolic macrocycle comprises the steps of:

(a) cyclizing, in the presence of an acid catalyst, a compound ofFormula II: ##STR7## wherein: Q represents identical alkyl groups,cycloalkyl groups having from 5 to 7 ring atoms, or aryl or heteroarylgroups having from 5 to 12 ring atoms and

R represents identical hydrogen, alkyl, alcohol or carbonyl-containinggroups;

with either (i) a planar cyclic co-reactant having a formula selectedfrom the group consisting of: ##STR8## wherein: R¹ -R⁴ are independentlyhydrogen, lower alkyl, alcohol, or carbonyl-containing groups;

Z and Z' are each --N--, >NH, --O-- or --S--;

Y is a direct link, alkylene, pyrrolylene, furanylene, phenylene,thiophenylene, benzylene, or alkylene-pyrrolene-alkylene;

X and X' are independently hydrogen or --COOH; and

G represents the atoms necessary to complete a carbocyclic orheterocyclic ring having from 5 to 14 ring atoms,

or (ii) a compound of Formula I: ##STR9## to form a cyclizedintermediate; and (b) oxidizing said cyclized intermediate to form thecorresponding 5,10-disubstituted porphyrin compound or other5,10-disubstituted polypyrrolic macrocycle.

BRIEF DESCRIPTION OF THE DRAWINGS

The present invention will be more clearly understood by referring tothe following drawings, in which:

FIG. 1 shows the formation of a number of tetrapyrrolic compounds.

FIG. 2 shows the formation of a number of pentapyrrolic compounds.

FIG. 3 shows the formation of a number of miscellaneous polypyrrolicmacrocyclic compounds.

FIG. 4 shows the ¹ H-NMR spectrum of a sublimation residue containing5,10-diphenyltripyrrane in CDCl₃.

DETAILED DESCRIPTION OF THE INVENTION

The meso-disubstituted tripyrrane compounds of the invention haveFormula I, as described and shown above. Q in Formula I can be any oneof a large number of alkyl groups, substituted or unsubstitutedcycloalkyl groups, substituted aromatic rings or substituted orunsubstituted heterocyclic rings, but should be chosen to have noadverse effect on the ability of the compound of Formula I to undergothe cyclization and oxidation reactins used to prepare the polypyrrolicmacrocycles of the invention.

When Q in Formula I is an alkyl group, it preferably has from about 1 toabout 18 carbon atoms, more preferably about 1 to 12 carbon atoms and,even more preferably, from about 1 to 6 carbon atoms. Examples of usefulalkyl groups are methyl, ethyl, isopropyl, sec-butyl, tert-butyl,n-pentyl and n-octyl.

When Q is a cycloalkyl group, it preferably contains from about 5 to 7carbon atoms. Examples of typical cycloalkyl groups include cyclopropyl,cyclohexyl and cycloheteroalkyl, such as glucopyranose or fructofuranosesugars. When Q is a cycloalkyl group, it may be unsubstituted orsubstituted with any group that does not interfere with the reactionstep (a), such as an aldehyde group, an acetal, or any other acid-labilegroup.

When Q is an aryl group, Q typically contains from about 5 to about 14carbon atoms, preferably about 5 to 12 carbon atoms and, optionally, cancontain one or more rings that are fused to the existing conjugatedpyrrolic ring structure. Examples of particularly suitable aromaticrings include phenyl, naphthyl, anthracenyl, phenanthrenyl, and thelike.

When Q is a heteroaryl group, Q typically contains from about 5 to 14ring atoms, preferably about 5 to 12 ring atoms, and one or moreheteroatoms. Examples of suitable heteroaryl groups include furan,thiophene, pyrrole, isopyrrole, 3-isopyrrole, pyrazole, 2-isoimidazole,1,2,3-triazole, 1,2,4-triazole, oxazole, thiazole, isothiazole,1,2,3-oxadiazole, 1,2,4-oxadiazole, 1,2,5-oxadiazole, 1,3,4-oxadiazole,1,2,3,4-oxatriazole, 1,2,3,5-oxatriazole, 1,2,3-dioxazole,1,2,4-dioxazole, 1,3,2-dioxazole, 1,3,4-dioxazole, 1,2,5-oxatriazole,1,3,-oxathiole, 1,2-pyran, 1,4-pyran, 1,2-pyrone, 1,4-pyrone,1,2-dioxin, 1,3-dioxin, pyridine, N-alkyl pyridinium, pyridazine,pyrimidine, pyrazine, 1,3,5-triazine, 1,2,4-triazine, 1,2,3-triazine,1,2,4-oxazine, 1,3,2-oxazine, 1,3,5-oxazine, 1,4-oxazine, o-isoxazine,p-isoxazine, 1,2,5-oxathiazine, 1,4-oxazine, 1,2,6-oxathiazine,1,4,2-oxadiazine, 1,3,5,2-oxadiazine, azepine, oxepin, thiepin,1,2,4-diazepine, indene, isoindene, benzofuran, isobenzofuran,thionaphthene, isothionaphthene, indole, indolenine, 2-isobenzazole,1,4-pyrindine, pyrando 3,4-b!-pyrrole, isoindazole, indoxazine,benzoxazole, anthranil, 1,2-benzopyran, 1,2-benzopyrone,1,4-benzopyrone, 2,1-benzopyrone, 2,3-benzopyrone, quinoline,isoquinoline, 1,2-benzodiazine, 1,3-benzodiazine, naphthyridine, pyrido3,4-b)-pyridine, pyrido(3,2-b!-pyridine, pyrido 4,3-b!-pyridine,1,3,2-benzoxazine, 1,4,2-benzoxazine, 2,3,1-benzoxazine,3,1,4-benzoxazine, 1,2-benzisoxazine, 1,4-benzisoxazine, carbazole,xanthrene, acridine, purine, and the like. Preferably, when Q is aheteroaryl group, it is selected from the group consisting of furan,pyridine, N-alkylpyridine, 1,2,3- and 1,2,4-triazoles, indene,anthracene and purine.

Preferably, Q is a phenyl or pyridinyl group substituted with one ormore non-interfering substituents having from 1 to 6 carbon atoms. Evenmore preferably, Q is a phenyl or pyridinyl group having the formula:##STR10## where A, A', B, B', C and C' can be any one of a large numberof substituents that are generally used to "fine tune" the biologicalactivity, biodistribution, solubility, absorption, clearancecharacteristics, and/or physical properties of the desired product.Preferably, substituents are selected in such a manner that thepolypyrrolic macrocyclic compound to be made from the tripyrrane ofFormula I will be an amphiphilic molecule. By "amphiphilic" is meantthat the molecule has become more asymmetric, such as

(1) having both (a) a highly polar water-soluble region and (b) a highlyhydrophobic, water-insoluble region;

(2) having both (a) a non-ionic region and (b) an ionic region; or

(3) having both (a) an anionic portion and (b) a cationic portion.

Preferably, A, A', B, B', C and C' are independently hydrogen, halogen,lower alkyl, lower alkoxy, hydroxy, carboxylic acid, cyano, nitro, orthe like. Most preferably, Q is a phenyl group that is eitherunsubstituted or substituted with a halogen atom.

R in Formula I can be any substituent that does not deactivate thepyrrole starting material in the synthesis of a compound of Formula I.For example, electron-withdrawing groups such as halogens and directlylinked oxygen should usually be avoided in this position. Preferably, Ris selected from the group consisting of hydrogen; lower alkyl such asmethyl, ethyl, n-propyl, i-propyl, n-butyl, and tert-butyl; alcoholssuch as --CH₂ OH and --(CH₂)₃ OH; carboxyl groups such as --CH₂ C(O)CH₃, --(CH₂)₂ COOH, --(CH₂)₂ COOCH₃, and --(CH₂)₂ COOC₂ H₅ ; and amidesof the formula --CO--NR'R" where R' and R" are independently hydrogen,alkyl or aryl. In a particularly preferred embodiment, R is eitherhydrogen or a lower alkyl group. Further, it is preferred that all Rgroups should be the same to prevent any confusion with regioisomers,unless the substituents confer the same regiochemical selectivity on theoutcome of the condensation.

The meso-disubstituted tripyrrane compound of Formula I is preferablymade by:

(a) reacting a compound of the formula:

    Q--CHO or Q--CH(OS)(OS')

wherein Q, S and S' are as defined above, with a stoichiometric excessof a pyrrole having the formula: ##STR11## in the presence of acatalytic amount of a strong Lewis or Bronsted acid; (b) removing theunreacted pyrrole and any other solvent used in step (a) by evaporationto form a residue;

(c) treating the residue to remove polymeric materials; and

(d) removing the corresponding dipyrromethane by-product from theresidue of step (c), leaving the compound of Formula I.

In the formula:

    Q--CHO or Q--CH(OS)(OS')

S and S' can be can be any one of a large number of substituents.Preferably, S and S' are independently lower alkyl, such as methyl,ethyl, i-propyl, t-butyl and n-pentyl; an aryl group containing from 5to 14 ring atoms, such as phenyl, naphthyl, pyridinyl, amidazolyl,furanyl, and the like; and --(CH₂)_(n) -- where n is 2, 3 or 4.

In the process of making the compound of Formula I, the molar ratio ofthe compound having the formula

    Q--CHO or Q--CH(OS)(OS')

and the pyrrole starting material can vary greatly between the ranges ofabout 2:3 to about 1:40, depending upon the solubility and reactivity ofthe reactants and products. Preferably, however, if the pyrrole is notsubstituted in the β-position, i.e., both R groups are hydrogens, anexcess amount of the pyrrole is used as the solvent and is, therefore,present in a much greater molar quantity than the compound Q--CHO orQ--CH(OS)(OS'). On the other hand, if the pyrrole has β-substituents(other than hydrogen), the use of another solvent, in addition to thepyrrole, is preferred, and the relative amount of the pyrrole will tendto be lower, i.e., from about 2:3 to about 1:10. Thus, an excess amountof the pyrrole starting material can be used as the solvent, and this isparticularly preferred where both R groups on the pyrrole molecule arehydrogens. However, an organic solvent other than the pyrrole can alsobe used in combination with the excess amount of the pyrrole present toform a mixed solvent, and this is particularly preferred where both Rgroups are not hydrogen.

When a solvent in addition to the pyrrole starting material is used, itcan be any one of a wide variety of organic solvents that is capable ofdissolving at least one of the reactants and, yet, does not interferewith the course of the reaction to any significant degree. Preferably,such a solvent should also have a boiling point sufficiently low toevaporate off with the excess pyrrole present in the evaporation step(b). Examples of such solvents include alcohols, such as methanol,ethanol, i-propanol, n-butanol, 2-ethylhexanol, benzyl alcohol, andglycerol; ethers such as diethyl ether, n-butyl ether anddimethoxyethane; aromatic solvents, such as benzene, toluene, andaniline; ketones such as acetone and methyl ethyl ketone; esters such asethyl acetate, butyl acetate, and ethyl benzoate; and chlorinatedsolvents such as carbon tetrachloride, chloroform, dichloromethane, and1,1,1-trichloroethane.

The strong Lewis or Bronsted acid of step (a) is generally used in onlycatalytic amounts. Particularly suitable strong Lewis or Bronsted acidsinclude mineral acids such as hydrobromic acid (HBr), hydrochloric acid(HCl), and sulfuric acid (H₂ SO₄); organic acids such as acetic acid;halogenated acids such as boron trifluoride etherate (BF₃ Et₂ O),trichloroacetic acid (CCl₃ COOH), trifluoroacetic acid (CF₃ COOH), andtriflic acid (CF₃ SO₃ H); and sulfonic acids such as benezenesulfonicacid and p-toluenesulfonic acid. Solid-phase, bound acids such as cationexchange resins and other polymeric acids or clays, such asmontmorillonite, may also be suitable strong acids to catalyze thereaction. In a particularly preferred embodiment, the strong Lewis orBronsted acid of step (a) is either p-toluenesulfonic acid ortrifluoroacetic acid.

In a preferred embodiment, the reaction takes place under an inertatmosphere to avoid oxidation or oxidative polymerization of thecomponents. When used, the inert atmosphere is usually provided byforming a protective blanket of an inert gas, such as argon, helium, orN₂, over the reaction mixture or bubbling an inert gas through it. Othermethods of providing an inert atmosphere include performing the reactionunder reduced pressure to form an atmosphere of solvent vapor(s).

The reaction temperature in step (a) can vary widely depending on thereactivity of the reactants. However, the temperature should not be sohigh as to decompose the reactants or so low as to cause inhibition ofthe condensation or freezing of the solvent. In most cases, the reactionin step (a) can take place at a temperature ranging from about roomtemperature, for reasons of convenience, to the reflux temperature ofthe reaction mixture, which typically varies from about 25 to about 150°C.

The time required for the reaction of the Q--CHO or Q--CH(OS)(OS')compound and the above-described pyrrole starting material will dependto a large extent on the temperature being used and the relativereactivities of the starting materials. Particularly when themeso-substituents are aryl, cycloalkyl, or a bulky alkyl group such astert-butyl, the time required for the reaction may increase due tosteric hindrance. Therefore, the reaction time can vary greatly, forexample, from about five minutes to about two days. Typically, the timerequired for the formation of the compound of Formula I is in the rangeof about five minutes to two hours, preferably, about 15 minutes.Various known techniques such as different types of chromatography,especially thin layer chromatography (TLC), gas chromatography (GC), oroptical spectroscopy can be used to follow the progress of the reactionby the disappearance of the starting Q--CHO or Q--CH(OS)(OS') compound.

In step (b) of the process of making the compound of Formula I, inaccordance with the invention, the unreacted portion of the pyrrole isremoved by evaporation to leave a residue containing the product.Preferably, this removal step by evaporation takes place under reducedpressure to increase the rate of evaporation and to reduce thetemperature necessary to evaporate off substantially all of theunreacted pyrrole.

At the conclusion of the evaporation step (b), a residue remains, fromwhich the meso-disubstituted tripyrrane can be isolated by anyconventional means, such as by chromatography, crystallization,re-crystallization, sublimation, various combinations of these methods,and the like. Typically, two primary types of impurities must be removedfrom the residue: (1) high molecular weight polymeric materials; and (2)the dipyrromethane molecule corresponding to the desired tripyrraneproduct, which occurs as a by-product of the above-described reaction.

Preferably, the isolation step (c) comprises a combination of twosteps--one to remove each major impurity. To remove the polymericmaterials, any conventional means may be used. The removal of polymericmaterial is preferred, at least to some extent, to increase the easeand/or rate of removal of the dipyrromethane by-product and to improveoverally product purity. However, after the evaporation step (b), it ispossible to remove the dipyrromethane by-product without requiring aseparate step to remove polymeric materials.

When these materials are removed from the residue, typically, theremoval is accomplished chromatographically. Preferably, a column ofsilica or alumina is used. Any eluting solvent that provides goodseparation on the column of choice may be used. Examples of particularlyuseful eluting solvents include chlorinated solvents such as chloroform,carbon tetrachloride, mixtures thereof and the like.

As to removal of the dipyrromethane by-product, any suitable andeffective means may be employed. However, sublimation is the preferredmethod. If sublimation is to be used to remove the dipyrromethaneby-product, the residue of step (b), which typically contains thecompound of Formula I and the corresponding dipyrromethane by-product,is slowly heated (usually at a rate of about 0.1 to about 2.0°C./minute, preferably about 0.50 to about 1.00° C./minute) until thesublimation temperature of the dipyrromethane by-product (usually about120-140° C. under reduced pressure) has been reached. It should be notedthat the desired compound is found in the sublimation residue and not inthe sublimate, as most often found in sublimation purifications.

Depending upon several factors, such as how much of the primaryimpurities, e.g., the corresponding dipyrromethane, other oligomers andpolymers, have already been removed from the residue and the volatilityof the dipyrromethane, the use of sublimation in step (c) fairly quicklyproduces a composition of more than 5%, i.e., from 5-100%, of thedesired tripyrrane, which also contains less than 95%, i.e., 0 to 95%,of the corresponding dipyrromethane contaminant. However, preferably,the composition contains more than 50%, i.e., from about 50-100%, morepreferably 95-100%, of the desired tripyrrane and less than 50%, morepreferably less than about 5%, of the corresponding dipyrromethane.

When sublimation is used in step (c), it preferably takes place underreduced pressure, more preferably from about 10 to about 0.01 mm Hg and,most preferably, at about 0.1 mm Hg. The sublimation temperature shouldbe sufficiently high to ensure an acceptable rate of sublimation,without being so high as to cause decomposition of the product orsublimation of the desired tripyrrane. The sublimation temperature willalso be affected by the pressure under which the sublimation is beingcarried out, with the temperature necessary for sublimation generallydecreasing as the pressure is reduced. At about 1 mm Hg, the temperaturetypically varies from about 120 to 140° C. and, preferably, ismaintained at about 130° C. Particularly when using the sublimationmethod of purification, the tripyrrane can be prepared in solid form ona large scale, can be fully characterized, and has excellent purity.

Generally, for example, a meso-disubstituted tripyrrane can besynthesized by stirring together the appropriately substituted aldehydeand the appropriate pyrrole in a molar ratio of about 1:20 with acatalytic amount of trifluoroacetic acid ("TFA") at room temperatureunder nitrogen for about 10-20 minutes. The excess pyrrole is evaporatedoff under vacuum, usually resulting in an oil.

In a preferred embodiment, the product is isolated to some extent, suchas by dissolving in an eluting solvent and chromatographed through ashort column of silica gel to remove polymeric material. If present, theeluting solvent is then evaporated off, and the residue is heated tosublime off the unwanted dipyrromethane, leaving the desiredmeso-disubstituted tripyrrane at about a 95% purity level. This methodis particularly favored when the tripyrrane is being made from aβ-unsubstituted pyrrole (where both R groups are hydrogens) and is basedon the method described by Lee et al., Tetrahedron, 50:39, 11427-40(1994).

Alternatively, a meso-disubstituted tripyrrane can be made by refluxingtogether the appropriately substituted aldehyde and an excess amount ofthe appropriate pyrrole in an organic solvent with a catalytic amount ofp-toluenesulfonic acid. This method is based on a procedure mentioned inthe notes and references section of Rebek et al., Tetrahedron Letters,35:37, 6823 (1994), which refer to T. Carell, Ph.D. thesis,Ruprechts-Karl-Universitat Heidelberg (1994). The reaction mixture isfiltered through silica, and the solvent is evaporated off. The residueis then heated to separate the two main products: the dipyrromethane andthe meso-disubstituted tripyrrane. As described above, it is theundesired dipyrromethane that sublimes off, leaving the desiredtripyrrane behind.

This second method is particularly suitable for preparing tripyrranesthat are made from a β-substituted pyrrole since, in these cases, thepyrrole is not generally relied upon as the sole solvent. Using eitherthe first or second method, however, about a 10% yield of a tripyrraneproduct that demonstrates excellent purity is achieved and by a processthat is amenable to large-scale synthesis of multi-gram quantities.

The meso-disubstituted tripyrrane compounds of Formula I may be easilyconverted to the corresponding dialdehyde under standard Vilsmeier-Haakconditions, as shown below: ##STR12##

By "standard Vilsmeier-Haak conditions" is meant the use of a eitherexcess dimethylformamide (DMF)/phosphoryl chloride (POCl₃) orDMF/benzoyl chloride, at 80° C. for 1-6 hours, followed by hydrolysis inaqueous sodium acetate and, if necessary, chromatography, in accordancewith A. Haussner et al., Organic Syntheses Based on Name Reactions andUnnamed Reactions, Pergamon, Oxford, 1st reprint, 399 (1995), thedisclosure of which is hereby incorporated by reference.

The meso-substituted tripyrrane compounds of the invention may bereacted with a wide variety of appropriately functionalized heterocyclicand carbocyclic rings to produce a large number of possible5,10-disubstituted porphyrins, expanded porphyrins, and miscellaneousother polypyrrolic macrocycles, all of which would be difficult to makeby any other known method. For example, a compound of Formula I can becyclized with a compound of Formula II, or two moles of a compound ofFormula I can be condensed with two moles of Q--CHO, seen above.

Specific examples of reactions of the compound of Formula I with aconsiderable number of different monopyrrolic heterocyclic reactants toform an array of polypyrrolic products are illustrated in FIG. 1. Themeso-disubstituted tripyrrane compounds of the invention may also bereacted with appropriately functionalized 5-membered, bi-heterocycliccompounds to produce a wide variety of possible 5,10-disubstitutedsapphyrins and pentaphyrins. Specific examples of possible reactionswith these bicyclic reactants to produce macrocyclic products areillustrated in FIG. 2.

Still other miscellaneous mono- or bicyclic, hetero- or carbocycliccompounds can be reacted with the meso-substituted tripyrrane compoundsto produce a great variety of pentaphyrins, hexaphyrins and texaphyrins.Specific examples of these reactants and products are illustrated inFIG. 3. Thus, the meso-disubstituted tripyrrane of Formula I may be usedas a key intermediate to make a large library of other polypyrroliccompounds, most of which are useful in the areas described above.

Generally speaking, the preparation of 5,10-disubstituted porphyrins andother 5,10-disubstituted polypyrrolic macrocycles includes two basicsteps:

(a) an acid-catalyzed cyclization step; and

(b) an oxidation step, typically, to form a fully conjugated macrocycle,which can often be performed in situ.

Typically, an additional step (c) is also used to isolate the product tosome extent.

In one embodiment, the cyclization step (a) involves the reaction of thetripyrrane compound of Formula I having two terminal pyrrole rings, eachhaving an unsubstituted α-position, with a planar cyclic co-reactanthaving a formula selected from the group consisting of: ##STR13## whereS and S' are as defined above, and Z and Z' are independently--N--, >NH, --O-- or a bivalent sulfur atom, preferably --N-- or >NH.

R¹ -R⁵ are independently hydrogen, lower alkyl, alcohol orcarbonyl-containing groups. Preferably, R¹ -R⁵ are selected from thegroup consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl,n-butyl, tert-butyl, --C₈ H₁₇, --OCH₃, --O(CH₂ CH₂ O)₃ CH₂ CH₃, --CH₂OH, --(CH₂)₄ OH, --O(CH₂)₃ OH, --(CH₂)₂ COOH, --(CH₂)₂ COOCH₃, and--(CH₂)₂ COOC₂ H₅.

X and X' in the above formulas are groups capable of coupling with theunsubstituted α-positions of the terminal pyrrole rings of the compoundof Formula I. Preferably, X and X' have the formula --CHO or --CHR'--Lwhere R' is hydrogen, alkyl such as methyl or ethyl, or aryl such asphenyl, pyridyl, or phenanthrenyl; and L is a good leaving group. By"leaving group" is meant a moiety, such as --NH₂, --OH or --OAc, that isreadily lost under acid catalysis to form a cationic intermediate, i.e.,a "--CH₂ ⁺ " group. This cationic intermediate then attacks in anucleophilic fashion the α-position of the tripyrrane. In a particularlypreferred embodiment, X and X' are selected from the group consisting of--CHO, --CH₂ OH, --CH₂ NH₂, and --CH(Ar)--OH where Ar is aryl havingfrom 5 to 7 ring carbons.

Y in the above formula can be a direct link, alkylene, pyrrolylene,furanylene, phenylene, thiophenylene, benzylene, oralkylene-pyrrolene-alkylene. However, preferably, Y is selected from thegroup consisting of a direct link, --CH₂ --, pyrrolene, furanylene,thiophenylene, benzylene and --CH₂ -pyrrolene-CH₂ --.

In the cyclization step (a), the molar ratio of the tripyrrane ofFormula I to the planar co-reactant can vary greatly between the rangesof about 10:1 to about 1:50, preferably from about 1:1 to about 1:2,depending upon the reactivity of the reactants.

Typically, a suitably non-reactive organic solvent is used to dissolveat least one of the starting materials, thus facilitating thecyclization reaction. When a solvent is used, it can be any one of awide variety of organic solvents capable of dissolving at least one ofthe reactants and, yet, does not interfere with the course of thereaction to any significant degree. Preferably, such a solvent shouldalso have a boiling point sufficiently low to evaporate off quicklyduring the process of isolating and/or purifying the product.

Examples of suitable solvents include alcohols, such as methanol,ethanol, i-propanol, n-butanol, 2-ethylhexanol, benzyl alcohol,glycerol, and dimethoxyethane; ethers such as diethyl ether and n-butylether; aromatic solvents, such as benzene, toluene, and aniline; ketonessuch as acetone and methyl ethyl ketone; esters such as ethyl acetate,butyl acetate, and ethyl benzoate; and chlorinated solvents such ascarbon tetrachloride, chloroform, dichloromethane, and1,1,1-trichloroethane.

A cyclization agent can be used in step (a) and, typically, is a Lewisor Bronsted acid. Examples of suitable cyclization agents includemineral acids such as hydrobromic acid (HBr), hydrochloric acid (HCl)and sulfuric acid (H₂ SO₄); other acids such as boron trifluorideetherate (BF₃ Et₂ O), acetic acid, trichloroacetic acid (CCl₃ COOH),trifluoroacetic acid (CF₃ COOH), and triflic acid (CF₃ SO₃ H); sulfonicacids such as benezenesulfonic acid, p-toluenesulfonic acid andtrifluoromethane sulfonic acid; metal halides such as SnCl₄, AlCl₃,FeCl₃, and fused zinc chloride; solid-phase, bound acids, such as cationexchange resins and other polymeric acids or clays, such asmontmorillonite; and mixtures of such cyclization reagents. In aparticularly preferred embodiment, the cyclization agent isp-toluenesulfonic acid, the etherate BF₃ Et₂ O or trifluoroacetic acid.

The cyclization agent can be present in widely varying amounts fromcatalytic amounts up to 0.01 to 10 times the molar amount of tripyrranepresent. Preferably, the acid is present in a molar concentrationranging from catalytic to about 5 times the molar amount of thetripyrrane.

Examples of particularly suitable combinations of cyclization agent andnon-reactive solvent include p-toluenesulfonic acid in ethanol; theetherate BF₃ Et₂ O or trifluoroacetic acid in dichloromethane; andp-toluenesulfonic acid in toluene.

The cyclization reaction temperature in step (a) can vary widelydepending on the solubility of the reactants in the solvent being used,the reactivity of the reactants and the thermal stability of thereactants. The temperature should not be so high as to decompose thereactants or so low as to inhibit the reaction or freeze the solution.In most cases, the reaction in step (a) can take place conveniently atroom temperature, and room temperature is preferred for reasons ofconvenience. However, occasionally, some heat is advantageous, primarilyto facilitate the dissolution of the starting materials being used inthe organic solvent employed.

The cyclization reaction can be carried out at pressures both above andbelow atmospheric pressure. Preferably, however, the reaction is carriedout at a pressure about equal to atmospheric pressure. The reaction canbe carried out in the presence of a mixture of gases approximating airbut, when particularly reactive reactants are involved, the gaseousmixture may be enriched with an inert gas, such as nitrogen gas, argonand the like.

The time required for the cyclization reaction of the tripyrrane ofFormula I and the above-described planar co-reactant will depend to alarge extent on the temperature used and the relative reactivities ofthe starting materials. Particularly when the meso-substituents of thetripyrrane compound are aryl, heteroaryl, or a bulky alkyl group such astert-butyl, the time required for the reaction to take place mayincrease due to steric hindrance. Therefore, the reaction time can varygreatly, for example, from about 30 minutes to about 24 hours.Preferably, the time required for the cyclization of the tripyrrane ofFormula I with the planar co-reactant is in the range of about 30 to 60minutes, unless the cyclization step (a) is combined with the oxidationstep (b), either sequentially or simultaneously. When (a) and (b) arecombined or occur simultaneously, the reaction time will be controlledby the time needed for the completion of both reactions and, typically,will be somewhat longer, for example, from about 8 to 25 hours, mostpreferably about 12 hours.

Optionally, various techniques such as different types ofchromatography, especially thin layer chromatography (TLC) or gaschromatography (GC), and optical spectroscopy, can be used to follow theprogress of the reaction by the disappearance of the starting materials.

At the conclusion of the cyclization reaction, a reaction mixtureresults, which is typically used directly in the oxidation step (b)without the intervening isolation or purification of the intermediate(s)present in the reaction mixture.

The oxidation of the cyclization reaction mixture to form the desired5,10-disubstituted porphyrin or other 5,10-disubstituted tetrapyrrolicmacrocyclic compound can be accomplished by any of the usual oxidizingagents generally suitable to accomplish this type of aromatization.Examples of such useful oxidizing agents includedichloro-dicyanobenzoquinone ("DDQ"), o- and p-chloranil, O₂ gas, iodine(I₂) and the like. Most of the above oxidizing agents are used incombination with the non-reactive organic solvent used during thecyclization step. Particularly preferred combinations of oxidizingagents and solvents for step (b) are selected from the group consistingof DDQ or p-chloranil in dichloromethane or toluene, or O₂ gas bubbledthrough an alcohol solvent such as methanol or ethanol.

The rate of the reaction is often influenced by the type and combinationof oxidizing agent and solvent, whether it takes place as a separatesequential step or occurs simultaneously with the cyclization step.Simultaneous cyclization and oxidation can take place with, for example,the simultaneous use of an alcohol solvent such as methanol or ethanol,an aromatic acid reactant such as p-toluenesulfonic acid, and oxygen gasbubbling through the reaction mixture. Other examples include thecombination of a solvent such as chloroform with air being used as theoxidizing agent.

The temperature of the reaction mixture during the oxidation step (b)can vary widely depending upon the oxidizing agent being used. Forexample, when DDQ in toluene is being used, reflux temperature isgenerally appropriate. On the other hand, when oxygen gas is being usedas the oxidizing agent with an ethanol solvent, ambient temperature is asuitable temperature. When other oxidizing agents are used, thetemperature is typically maintained in the range of about 1 to 100° C.and, preferably, is allowed to remain at about room temperature or atthe reflux temperature of the reaction mixture.

The time required for the oxidation reaction of step (b) will depend toa large extent on the temperature used and the relative reactivities ofthe starting materials being used. However, the time typically variesfrom about 15 minutes to about 24 hours, usually from about 20 minutesto an hour for room temperature reactions. If the oxidation takes placesimultaneously with the cyclization reaction, as described above, thetime required for both reactions can be as long as two days but,usually, is about 10 to 15 hours.

The oxidation reaction of step (b) can be carried out in the presence ofgases at a pressure both above and below atmospheric pressure. Mostfrequently, however, the reaction is carried out at a pressure aboutequal to atmospheric pressure.

The resulting product, a 5,10-disubstituted porphyrin or other5,10-disubstituted polypyrrolic macrocyclic compound, can be isolated byany conventional method, such as by drowning out in a non-solvent,precipitating out, extraction with any immiscible liquid, evaporation ofa solvent, or some combination of these or other conventional methods.Typically, after being isolated, the product is then purified by anyone, or a combination, of known purification techniques, such asrecrystallization, various forms of chromatography, trituration with anon-solvent or a partial solvent, vacuum distillation, countercurrentextraction techniques, and the like.

It is preferable to isolate and/or purify the 5,10-disubstitutedporphyrin or other 5,10-disubstituted polypyrrolic macrocycle by the useof chromatography. For example, the resulting oil or solid productobtained after the oxidation step (b) (usually by evaporation of anysolvent used in the cyclization and/or oxidation) is dissolved in aneluting solvent and chromatographed through a column of silica gel oralumina to remove impurities. The appropriate fractions are collected,and the eluting solvent is then evaporated off, leaving the product asthe residue.

In an alternative embodiment, an α,α'-dialdehyde tripyrrane of FormulaII is cyclized in step (a), in the presence of an acid catalyst, witheither

(i) a planar cyclic co-reactant having a formula selected from the groupconsisting of: ##STR14## wherein: R¹ -R⁴, Z and Z', and Y are asdescribed above;

X and X' are independently hydrogen or --COOH; and

G represents the atoms necessary to complete a carbocyclic orheterocyclic ring having from 5 to 14 ring atoms, or

(ii) a compound of Formula I, to form a cyclized intermediate, which isthen oxidized to form the corresponding 5,10-disubstituted porphyrincompound or other 5,10-disubstituted polypyrrolic macrocycle. Thedialdehyde tripyrrane of Formula II can be prepared from theα,α'-unsubstituted tripyrrane of Formula I under standard Vilsmeier-Haakconditions, as described above.

In the cyclization step (a), the molar ratio of the tripyrrane ofFormula II to the planar co-reactant can vary greatly, depending uponthe reactivity of the reactants.

Typically, a suitably non-reactive organic solvent is used to dissolveat least one of the starting materials, thus facilitating thecyclization reaction. When a solvent is used, it can be any one of awide variety of organic solvents capable of dissolving at least one ofthe reactants and, yet, does not interfere with the course of thereaction to any significant degree. Preferably, such a solvent shouldalso have a boiling point sufficiently low to evaporate off quicklyduring the process of isolating and/or purifying the product.

Examples of suitable solvents include alcohols, such as methanol,ethanol, i-propanol, n-butanol, 2-ethylhexanol, benzyl alcohol,glycerol, and dimethoxyethane; ethers such as diethyl ether and n-butylether; aromatic solvents, such as benzene, toluene, and aniline; ketonessuch as acetone and methyl ethyl ketone; esters such as ethyl acetate,butyl acetate, and ethyl benzoate; chlorinated solvents such as carbontetrachloride, chloroform, dichloromethane, and 1,1,1-trichloroethane;and the like.

A cyclization agent can be used in step (a) and, typically, is a Lewisor Bronsted acid. Examples of suitable cyclization agents includemineral acids such as hydrobromic acid (HBr), hydrochloric acid (HCl)and sulfuric acid (H₂ SO₄); other acids such as boron trifluorideetherate (BF₃ Et₂ O), acetic acid, trichloroacetic acid (CCl₃ COOH),trifluoroacetic acid (CF₃ COOH), and triflic acid (CF₃ SO₃ H); sulfonicacids such as benezenesulfonic acid, p-toluenesulfonic acid andtrifluoromethane sulfonic acid; metal halides such as SnCl₄, AlCl₃,FeCl₃, and fused zinc chloride; solid-phase, bound acids, for example,cation exchange resins, and other polymeric acids and clays, such asmontmorillonite clay, and mixtures of such cyclization reagents. In aparticularly preferred embodiment, the cyclization agent isp-toluenesulfonic acid, the etherate BF₃ Et₂ O, or trifluoroacetic acid.

The cyclization agent can be present in widely varying amounts fromcatalytic amounts up to several times the molar amount of tripyrranepresent.

Examples of particularly suitable combinations of cyclization agent andnon-reactive solvent include p-toluenesulfonic acid in ethanol; theetherate BF₃ Et₂ O or trifluoroacetic acid in dichloromethane;p-toluenesulfonic acid in toluene; and the like.

The cyclization reaction temperature in step (a) can vary widelydepending on the solubility of the reactants in the solvent being used,the reactivity of the reactants, and the thermal stability of thereactants. The temperature should not be so high as to decompose thereactants or so low as to inhibit the reaction or to freeze thesolution. In most cases, the reaction in step (a) can take placeconveniently at room temperature, and room temperature is preferred forreasons of convenience. However, occasionally, some heat isadvantageous, primarily to facilitate the dissolution of the startingmaterials being used in the organic solvent employed.

The cyclization reaction can be carried out at pressures both above andbelow atmospheric pressure. Preferably, however, the reaction is carriedout at a pressure about equal to atmospheric pressure. The reaction canbe carried out in the presence of a mixture of gases approximating airbut, when particularly reactive reactants are involved, the gaseousmixture may be enriched with an inert gas, such as nitrogen gas, argonand the like.

The time required for the cyclization reaction of the tripyrrane ofFormula I and the above-described planar co-reactant will depend to alarge extent on the temperature used and the relative reactivities ofthe starting materials. Particularly when the meso-substituents of thetripyrrane compound are aryl, heteroaryl, or a bulky alkyl group such astert-butyl, the time required for the reaction to take place mayincrease due to steric hindrance. Therefore, the reaction time can varygreatly, for example, from a few minutes to several hours. When steps(a) and (b) are combined or occur simultaneously, the reaction time willbe controlled by the time needed for the completion of both reactionsand, typically, will be somewhat longer, for example, from several hoursto several days.

Optionally, various techniques such as different types ofchromatography, especially thin layer chromatography (TLC), gaschromatography (GC) or optical spectroscopy, can be used to follow theprogress of the reaction by the disappearance of the starting materials.The macrocycles initially formed will, if applicable, be readilyoxidized to the corresponding aromatic compound. The isolation andpurification procedures for this embodiment are equivalent to thosedescribed for the resulting macrocycle above.

Examples of macrocycles that can be made by one of the above methodsinclude:

3,22-diethyl-2,23-dimethyl-10,15-diphenylsapphyrin;

5,10-diphenylsapphyrin;

5,10,15,20-tetraphenylsapphyrin;

5,10,15,20,25,30-hexaphenylhexaphyrin;

17,23-diethyl-18,22-dimethyl-5,10-diphenylpentaphyrin; and

18,22-dithyl-17,22-dimethyl-5,10-diphenyl pentaphyrin.

The invention will be further clarified by the following examples, whichare intended to be purely illustrative of the invention.

EXAMPLE 1 Preparation of 5,10-Diphenyltripyrrane(4) ##STR15## Method A:(Particularly applicable to an unsubstituted pyrrole starting material):

6.0 ml of benzaldehyde (1) (59 mmol) was mixed with 150 ml of pyrrole(2) (2.16 mol), and the resulting mixture was deoxygenated by bubblingdry N₂ through it for 15 minutes. While still under nitrogen, 0.45 ml oftrifluoroacetic acid (5.8 mmol) was added, and the reaction mixture wasstirred for 15 minutes at room temperature (about 20° C.). After this,the reaction mixture was evaporated under vacuum (5 torr) with slightheating on a rotary evaporator to yield a dark oil. The oil was taken upin a minimal amount of methylene chloride and charged onto a flashchromatography column (silica gel, 5.5×30 cm., methylene chloride). Thecolorless fractions containing the dipyrromethane (3), the tripyrrane(4), and some small amounts (≦1%) of an unidentified material werecollected. Thin layer chromatography ("TLC") was used to follow theprocess in this manner: The TLC plates used were commercially availableMerck silica TLC aluminum sheets (silica gel 60 F₂₅₄). Upon treatmentwith fuming Br₂, the TLC spot corresponding to the dipyrromethane (3)turned bright orange, and the spot corresponding to the desiredtripyrrane (4) turned beige. The collected fractions were placed on arotary evaporator to evaporate off the solvent, yielding a tan oil.

It was found that the dipyrromethane (3) and tripyrrane (4) could beseparated in very small batches (100 mg) of the tan oil by the use ofprepared TLC plates made with a 1.0 mm silica coating and using CH₂ Cl₂/CCl₄ (1:1) as the eluting solvent. Specifically, the TLC plates usedwere pre-coated Whatman or Merck silica gel plates (available with orwithout fluorescence indicator), 20×20 cm; 0.5, 1.0 or 2.5 mm thickness.The R_(f) value for the desired tripyrrane (4) was 0.63; the R_(f) valuefor the dipyrromethane (3) was 0.78. However, this chromatographicmethod would not be useful for preparing even multiple-gram quantities,let alone industrial scale quantities.

The remainder of the tan oil was transferred into a sublimationapparatus and subjected to a high vacuum (0.1 torr). A slow heating rate(about 0.75° C./minute) was maintained until visible sublimation beganat 130° C. After all sublimation ceased, a white crystalline sublimate,consisting of 7.20 g of the dipyrromethane (3) (54.6% yield), wascollected, leaving 2.45 g (11% yield) of an orange, glassy sublimationresidue, which consisted mainly of the desired tripyrrane 4. The levelof purity was ≧95%, based on an ¹ H-NMR spectrum of the residue inCDCl₃, as shown in FIG. 4.

Method B: (Particularly applicable to β-substituted pyrrole startingmaterials):

12.0 ml of benzaldehyde (1) (0.118 mol) was dissolved in 750 ml oftoluene with 52 ml of pyrrole (2) (0.745 mol). A catalytic amount (100mg) of p-toluenesulfonic acid monohydrate (4.9×10⁻⁴ mol) was added tothe solution, and the reaction mixture was refluxed under N₂ for onehour. After this, the reaction mixture was evaporated on a rotaryevaporator to give a dark oil. The oil was subjected to much the samechromatography/sublimation treatment as described above for Method A.Specifically, the reaction mixture was filtered through silica, and thesolvent was evaporated off. The residue was then heated to separate thetwo products: the phenyl dipyrromethane and the meso-diphenyltripyrrane.The dipyrromethane sublimed off, leaving the tripyrrane behind as alight tan glass material. This gave a 44% yield of the dipyrromethane(3) and 9.8% of the desired tripyrrane at the same purity levelsproduced above in Method A (about 98%).

Analytical Data for Tripyrrane:

mp: 75-80° C.;

¹ H^(NMR) (200 MHz, CD₂ Cl₂): 5.35 (s, 2H), 5.78 (d, J=4 Hz, 2H), 5.89(s, 2H), 6.14 (dd, second order, J=4.4 Hz, 2H), 6.66 (dd, second order,J=4.4 Hz, 2H), 7.15-7.38 (m, 10H), 7.75 (br s, 1H), 7.88 (br s, 2H)

¹³ H-NMR (50 MHz, CDCl₃): 44.1, 107.2, 107.4, 108.4, 117.2, 127.0,128.4, 128.6, 132.3, 132.5, 142.1

HR-MS (EI, 200° C. : Expected for ¹² C₂₆ H₂₃ N₃ : 377.1892; found377.1881.

    ______________________________________    Elemental Analysis for C.sub.26 H.sub.23 N.sub.3 (377.49 g/mol)    Element:    C            H      N    ______________________________________    Calculated: 82.73        6.14   11.13    Found:      82.16        6.03   10.72    ______________________________________

EXAMPLE 2 Preparation of3,22-Diethyl-2,23-dimethyl-10-15-diphenylsapphyrin (6) ##STR16##

22.6 mg of the tripyrrane (4) (6.0×10⁻⁵ mol) and 16.3 mg ofbipyrrolebis(aldehyde) (5) (6.0×10⁻⁵ mol) were dissolved in 60 ml ofabsolute ethanol, and O₂ was bubbled through the solution. 45.6 mg ofp-toluenesulfonic acid monohydrate (2.4×10⁻⁴ mol) was added, and O₂bubbling was continued for 12 hours. The solution was then evaporated ona rotary evaporator to dryness. The resulting solid was chromatographedon alumina (neutral, activity I, 2×12 cm) with 2.5% MeOH/CH₂ Cl₂. Theyellow-green main fraction was collected, and the solvent was evaporatedoff to give 14.3 mg of the product (6) as the free base (39% yield). Thefree base was quantitatively converted into its corresponding dark greenbis-hydrochloride by shaking a CHCl₃ solution of product (6) with a 20%aqueous HCl solution, followed by the addition and separation of anorganic phase, drying over anhydrous Na₂ SO₄, and evaporating todryness.

Analytical Data:

mp: ≧250° C.;

HR-MS (EI, 210° C.): Calculated for ¹² C₄₂ H₃₉ N₅ : 613.32056; found:613.31842

¹ H-NMR (200 MHz, CDCl₃) of the dihydrochloride: -4.48 (s, 2H), -4.36(s, 2H), -3.87 (s, 1H), 2.20 (tr, J=5.2 Hz, 6H), 4.18 (s, 6H), 4.58 (q,J=5.2 Hz, 4H), 7.90-8.05 (m, 6H), 8.61 (d, J=4.4 Hz, 4H), 9.28 (d, J=0.8Hz, 2H), 9.57 (dd, J=3.2, 0.8 Hz, 2H), 10.20 (dd, J=3.2, 0.8 Hz, 2H),11.78 (s, 2H)

UV-Vis CH₂ Cl₂, trace of Et₃ N! λ_(max) (rel. intensity): 458(1.0),626(0.43), 652(0.45), 684(0.54), 718(0.49), 802(0.14)

UV-Vis CH₂ Cl₂, trace of TFA! λ_(max) (rel. intensity): 486(1.0),772(0.28)

EXAMPLE 3 Preparation of 5,10-diphenylsapphyrin (8) ##STR17##

188 mg of the tripyrrane (4) (4.99×10⁻⁴ mol) and 94 mg ofbipyrrolebis(aldehyde) (7) (5.0×10⁻⁴ mol) were dissolved with the use ofa heat gun in 450 ml of absolute ethanol, and O₂ was bubbled through thesolution. 95 mg of p-toluenesulfonic acid monohydrate (2.0×10⁻³ mol)dissolved in 3 ml of ethanol were added, and the reaction mixture wasbubbled with O₂ for an additional 12 hours. After this, the reactionmixture was evaporated on a rotary evaporator to dryness. The resultingblack residue was triturated with CHCl₃. The combined dark greenextracts were evaporated to dryness and chromatographed on a preparedTLC plate (0.5 mm alumina) with 0.1% Et₃ N/CH₂ Cl₂. The green-yellowband was collected and eluted with 0.5% MeOH/CH₂ Cl₂. The solvent wasevaporated off to give 14.8 mg of the product (8) (5.5% yield). Theproduct (8) was converted quantitatively into its correspondingdihydro-p-toluenesulfate by adding a slight excess of p-toluenesulfonicacid to a CHCl₃ solution of product (8), followed by precipitation ofthe salt by slow diffusion of hexane into this solution.

Analytical Data:

¹ H-NMR (400 MHz, CDCl₃) of the bis(p-toluenesulfate) salt: -4.68 (s,2H), -4.46 (s, 2H), -3.85 (s, 1H), 2.45 (s, 6H), 7.26 (d, J=8 Hz, 4H),7.79 (d, J=8 Hz, 4H), 7.95-8.05 (m, 6H), 8.66 (d, J=7 Hz, 4H), 9.32 (d,J=0.8 Hz, 2H), 9.64 (dd, J=3.9, 0.9 Hz, 2H), 10.25 (dd, J=4.7, 0.9 Hz,2H), 10.47 (dd, J=4.7, 0.7 Hz, 2H), 10.78 (dd, J=4.4, 0.8 Hz, 2H), 11.92(s, 2H)

HR-MS (EI, 180° C.):

Calculated for ¹² C₃₆ H₂₅ N₅ : 527.21100; found: 527.21015

UV-Vis CH₂ Cl₂, trace of Et₃ N! λ_(max) (rel. intensity): 384, 478(1.0),506(0.69), 626, 686, 708, 786

UV-Vis CH₂ Cl₂, trace of TFA! λ_(max) (rel. intensity): 494(1.0), 656,682, 724(sh), 758(0.21)

EXAMPLE 4 Preparation of 5,10,15,20-tetraphenylsapphyrin (10) ##STR18##

75 mg of the tripyrrane (4) (2.00×10⁻⁴ mol), 42.4 mg of benzaldehyde (7)(4.0×10⁻⁴ mol), and 26.4 mg of the bipyrrole (9) (2.0×10⁻⁴), weredissolved in 20 ml of CH₂ Cl₂, and N₂ was bubbled through the solutionfor 15 minutes. One drop of BF₃ Et₂ O was added, and the solution wasstirred for one hour under N₂. Following this, 100 mg of p-chloranil(4.0×10⁻⁴) was added, and the reaction mixture was refluxed for 20minutes. The solution was charged onto a plug of alumina (basic,activity I, 2×5 cm) and filtered. The filtrate was evaporated todryness, and the resulting solid was chromatographed on a prepared TLCplate (0.5 mm alumina) with 1:1 CCl₄ /CH₂ Cl₂. The green band wascollected and eluted with CH₂ Cl₂. The solvent was evaporated off togive 7.4 mg of the product (10) as a bright green microcrystallinematerial (5.5% yield). By UV-Vis, MS, and NMR of the protonated andnon-protonated forms, the material was proved to be identical to5,10,15,20-tetraphenylsapphyrin, as described by Chmielewski et al.,Eur. J. Chem., 1:1, 68-73 (1995).

Analytical Data:

HR-MS (EI, 250° C.) Calculated for ¹² C₄₈ H₃₃ N₅ : 679.27362; found:679.27357

UV-Vis CH₂ Cl₂, trace of Et₃ N! λ_(max) (log epsilon): 492(4.01),518(3.80), 638(3.90), 698(3.16), 718(sh), 798(3.88)

UV-Vis CH₂ Cl₂, trace of TFA! λ_(max) (rel. intensity): 488(1.0),410(sh), 672(0.06), 736(0.11), 790(0.18)

EXAMPLE 5 Preparation of 5,10,15,20,25,30-hexaphenylhexaphyrin (11)##STR19##

75 mg of the tripyrrane (4) (2.00×10⁻⁴ mol) and 20 μl of benzaldehyde(1) (2.0×10⁻⁴ mol) were dissolved in 50 ml of CH₂ Cl₂. After thesolution was purged with N₂ for 10 minutes, 15 μl of trifluoroaceticacid was injected, and the mixture was stirred for 50 minutes. 91 mg ofdichlorodicyano-p-quinone (4.0×10⁻⁴ mol) was added, and the mixture wasstirred for an additional hour. The solvent was removed by evaporatingon a rotary evaporator, and the resulting solid was repeatedlychromatographed on prepared TLC plates (0.5 mm silica). The elutingsolvent was 20% EtOAc in CH₂ Cl₂ with a few drops of Et₃ N added. Theblue band, consisting of the product (11), was isolated and eluted.

Analytical Data:

HR-MS (EI, 350° C.):

Calculated for ¹² C₆₆ H₄₄ N₆ : 920.36273; found: 920.36550

UV-Vis CH₂ Cl₂ ! λ_(max) (rel. intensity): 385(0.95), 466(0.46),520(0.50), 636(1.0)

The ¹ H-NMR spectrum was complex, which may reflect a non-staticconfirmation. This has also been observed for β-alkyl hexaphyrins (seeCharriere et al., Heterocycles, 36:7, 1561 (1993)) and the sapphyrin(10) (see Chmielewski et al., Eur. J. Chem., 1:1, 68-73 (1995)). Becausethe compound (11) incorporates some structural elements from each ofthese compound classes, a dynamic conformation is likely.

EXAMPLE 6 Preparation of 5,10-diphenyltripyrrane-1,14-dicarboxaldehyde##STR20##

212 mg of the tripyrrane (4) (56 μmol) were dissolved in 5 ml of DMF,and the solution was stirred under an atmosphere of nitrogen. 71 μl ofphosphoryl chloride was injected, and the mixture was heated at 80° C.for one hour. 20 ml of water and 250 mg of potassium carbonate wereadded, and the mixture was heated for a further 30 minutes at 80° C. Thecrude mixture was poured into 50 ml of water and extracted three timeswith 100 ml of ethyl acetate. The combined organic phases were washedwith water (5×100 ml), dried over anhydrous sodium sulfate, andevaporated in vacuo. The residue was chromatographed on silica gel,eluting with 1:1 methylene chloride/ethyl acetate containing 1% triethylamine. 50 mg of analytically pure dialdehyde (12) was obtained bypreparative thin layer chromatography (silica gel; 2 mm), eluting with40% ethyl acetate in methylene chloride containing 1% triethyl amine(21% yield).

Analytical Data:

¹ H-NMR (CDCl₃): δ 9.8 (br s, 2H), 9.0 (s, 2H), 8.65 (br s, 1H), 7.2-7.1(m, 10H), 6.75 (m, 2H), 6.0 (m, 2H), 5.8 (s, 2H), 5.4 (s, 2H)

HR-MS (EI): Calculated for ¹² C₂₈ H₂₃ N₃ O₂ : 433.1790; found: 433.1794

EXAMPLE 7 Preparation of18,22-diethyl-17,22-dimethyl-5,10-diphenylpentaphrin (13) ##STR21##

37 mg of the tripyrrane (4) (1.00×10⁻⁴ mol) and a stoichiometric amountof dipyrromethane dialdehyde (12) are dissolved in 20 ml of ethanol. Themixture is stirred, and 50 mg of p-toluenesulfonic acid are added. Afterabout two hours, three equivalents of dichlorodicyanobenzoquinone("DDQ") are added. After additional stirring for two hours, the opticalspectrum of the mixture was characterized by a strong Soret band at 450nm and side bands at 528, 90 and 760 nm, all of which are indicative ofthe formation of the desired pentaphyrin in high yields.

We claim:
 1. A method for making a compound of Formula I: ##STR22##wherein: Q represents identical alkyl groups, cycloalkyl groups, arylgroups, or heteroaryl groups; and R represents identical hydrogen,alkyl, alcohol or carbonyl-containing groups; said method comprising thesteps of:(a) reacting a compound of the formula:

    Q--CHO or Q--CH(OS)(OS')

wherein S and S' are independently lower alkyl, an aryl or heteroarylgroup containing from 5 to 14 ring atoms, and --(CH₂)_(n) -- wheren=2-4; with a stoichiometric excess of a pyrrole having the formula:##STR23## in the presence of a catalytic amount of an acid; (b) removingthe unreacted pyrrole or any other solvents used in (a) by evaporationto form a residue; and (c) treating the residue to remove high molecularweight polymeric materials and the corresponding dipyrromethaneby-product, leaving the compound of Formula I.
 2. The method of claim 1wherein an excess molar amount of said pyrrole is used as a solvent. 3.The method of claim 1 wherein an organic solvent other than said pyrroleis used in combination with the excess of said pyrrole to form a mixedsolvent.
 4. The method of claim 1 wherein the reaction in step (a)thereof takes place at room temperature.
 5. The method of claim 1wherein the unreacted portion of said pyrrole and any other solventsused in step (a) thereof are removed by evaporation in step (b) thereof,under reduced pressure to form a residue.
 6. The method of claim 1wherein the residue is treated in step (c) thereof to remove saidpolymeric materials chromatographically.
 7. The method of claim 1wherein the residue of step (b) thereof is sublimed in step (c) thereof.8. The method of claim 7 wherein the subliming step is performed underreduced pressure.
 9. A process for making a meso substitutedpolypyrrolic macrocycle, said process comprising the steps of:(a) firstproducing a compound of the formula I, having two terminal pyrrolerings, each with an unsubstituted α-position, ##STR24## wherein Qrepresents identical alkyl groups, cycloalkyl groups, aryl groups, orheteroaryl groups; and R represents identical hydrogen, alkyl, alcoholor carbonyl-containing groups, by (a₁) reacting a compound of theformula:

    Q--CHO or Q--CH(OS)(OS')

wherein S and S' are independently lower alkyl, an aryl or heteroarylgroup containing from 5 to 14 ring atoms, and --(CH₂)_(n) -- wheren=2-4; with a stoichiometric excess of a pyrrole having the formula:##STR25## in the presence of a catalytic amount of an acid; (a₂)removing the unreacted pyrrole or any other solvents used in (a) to forma residue; (a₃) treating the residue to remove any high molecular weightpolymeric materials and the corresponding dipyrromethane by-product,thereby leaving the compound of Formula I; and then (b) cyclizing saidcompound of Formula I with a compound having a formula selected from thegroup consisting of:(1) Q'--CHO, wherein Q' is an alkyl group,cycloalkyl group, aryl group, or heteroaryl group; (2) Q'--CH(OS)(OS'),wherein Q' is an alkyl group, cycloalkyl group, aryl group, orheteroaryl group; ##STR26## wherein: S and S' are independently loweralkyl, an aryl group containing from 5 to 14 ring atoms, and --(CH₂)_(n)-- where n=2 to 4; R¹ -R⁵ are independently hydrogen, lower alkyl,alcohol or carbonyl-containing groups; X and X' are groups capable ofcoupling with the unsubstituted α-positions of the terminal pyrrolerings of the compound of Formula I; Z and Z' are independently--N--, >NH, --O-- or a bivalent sulfur atom; and Y is a direct link,alkylene, pyrrolylene, furanylene, phenylene, thiophenylene, benzylene,or alkylene-pyrrolene-alkylene, to form a cyclized intermediate; and (c)oxidizing the cyclized intermediate to form the correspondingsubstituted polypyrrolic macrocycle.
 10. The process of claim 9 whereinR¹ -R⁵ are selected from the group consisting of hydrogen, methyl,ethyl, n-propyl, i-propyl, n-butyl, tert-butyl, --C₈ H₁₇, --OCH₃,--O(CH₂ CH₂ O)₃ CH₂ CH₃, --CH₂ OH, --(CH₂)₄ OH, --O(CH₂)₃ OH, --(CH₂)₂COOH, --(CH₂)₂ COOCH₃, and --(CH₂)₂ COOC₂ H₅.
 11. The process of claim 9wherein Y is selected from the group consisting of a direct link, --CH₂--, pyrrolene, furanylene, thiophenylene, benzylene and --CH₂-pyrrolene-CH₂ --.
 12. The process of claim 9 wherein X and X' have theformula --CHO or --CHR'--L where R' is H, alkyl or aryl, and L is aleaving group.
 13. The process of claim 9 wherein X and X' are selectedfrom the group consisting of --CHO, --CH₂ OH, --CH₂ NH₂, and--CH(Ar)--OH where Ar is aryl having from 5 to 7 ring carbons.
 14. Theprocess of claim 9 further comprising, as step (c), purifying theresulting macrocycle.
 15. The process of claim 9, wherein said resultantpolypyrrolic macrocycle is a 5,10 meso-disubstituted compound.
 16. Theprocess of claim 9, wherein the cyclizing in step (a) thereof isperformed in the presence of an acid catalyst.
 17. The process of claim9, wherein group Q in Formula I is an aryl or heteroaryl groupcontaining from about 5 to about 14 ring atoms.
 18. The process of claim9, wherein group Q in Formula I is an alkyl group containing from about1 to about 18 carbon atoms.
 19. The process of claim 9, wherein group Qin Formula I is a cycloalkyl group containing from about 5 to 7 carbonatoms.
 20. The process of claim 9, wherein group Q in Formula I is arylor heteroaryl.
 21. The process of claim 9 wherein group Q in formula Iis phenyl or pyridinyl having one or more substituents selected from thegroup consisting of halogen, lower alkyl, lower alkoxy, hydroxy, cyano,nitro, or a carboxylic acid.
 22. The process of claim 9 wherein group Qin Q--CHO or Q--CH(OS)(OS') is selected from the group consisting of: anaryl or heteroaryl group containing from about 5 to about 14 ring atoms;an alkyl group containing from about 1 to about 18 carbon atoms; and acycloalkyl group containing from about 5 to 7 carbon atoms.
 23. Theprocess of claim 9 wherein R in Formula I thereof is selected from thegroup consisting of hydrogen, lower alkyl, an alcohol, acarboxy-containing group, and an amide of the formula --CO--NR'R"wherein R' and R" are each independently hydrogen, alkyl, or aryl. 24.The process of claim 9 wherein X and X' have the formula --CHO or--CHR'L where R' is hydrogen, alkyl, or aryl, and L is a leaving groupreadily lost under conditions of acid catalysis.